The antiandrogenic action of gonadotropin-releasing hormone and its agonists on the mouse kidney.

Abstract

It was recently demonstrated that GnRH and its agonists can inhibit the growth-promoting effects of testosterone on the prostate and seminal vesicle of the rat. In the present study, the kinetics and mechanism of this antiandrogenic response were investigated on the mouse kidney, an organ that has been used extensively to investigate androgen action. GnRH and its agonist, [(imBzl)-D-His6,Pro9-NEt]GnRH (D-His), inhibited the increase in kidney β-glucuronidase activity induced by testosterone propionate (TP) in castrated male mice. D-His also inhibited the action of TP on this enzyme in castrated hypophysectomized male mice. When D-His (10 μgday) was administered with various doses of TP (20–160 μg/day), the dose-dependent increase in β-glucuronidase activity was blunted. Similarly, D-His (0.1–100 μg/day) produced a dose-dependent decrease in the renal β-glucuronidase activity of castrated male mice treated with TP (80 μg/day). Even though GnRH and its agonist inhibited the action of TP in male NCS and Balb/C mice, these peptides slightly potentiated the action of TP on renal β-glucuronidase activity in female mice of these strains. D-His did not compete with [3H]methyltrienolone for binding sites on the androgen receptor as measured in an in vitro assay. In addition, the administration of D-His with TP in vivo did,not affect the total cytosol receptor activity as measured with an exchange assay. It is concluded that the antiandrogenic actions of GnRH and its agonists are not mediated via the androgen receptor in a manner comparable to that of steroid antagonists since 1) no competition between peptide and steroid could be demonstrated for the androgen receptor, and 2) the inhibitory actions of GnRH peptides were not uniform between the kidneys from male and female mice, which are equally sensitive to testosterone. The finding that GnRH has antisteroidal activity on the kidney and other tissues raises the possibility that this, or a similar peptide, could act as a local regulator of hormone action on extragonadal organs.